Process for preparing imidazo[1,5-a][1,5]benzodiazepines

ABSTRACT

The present invention concerns compounds of the formula   &lt;IMAGE&gt; wherein X is hydrogen or halogen; R1 is hydrogen, halogen or trifluoromethyl; R2 is hydrogen or lower alkyl; and R3 is hydrogen, -COO lower alkyl or CON(R4)2 wherein R4 is lower alkyl or hydrogen and may be different, AND THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF.

This is a division of application Ser. No. 775,347 filed Mar. 7, 1977,now U.S. Pat. No. 4,080,323.

DESCRIPTION OF THE INVENTION

The present invention relates to compounds of the formula ##STR2##wherein X is hydrogen or halogen; R₁ is hydrogen, halogen ortrifluoromethyl; R₂ is hydrogen or lower alkyl; and R₃ is hydrogen,--COO lower alkyl or CON(R₄)₂ wherein R₄ is lower alkyl or hydrogen andmay be different,

And the pharmaceutically acceptable salts thereof.

By the term "halogen" or "halo" is meant chloro, bromo, iodo and fluorosubstituents.

By the term "lower alkyl" is meant both straight chain and branchedchain (C₁ -C₇) carbon-hydrogen radicals, preferably C₁ -C₄carbon-hydrogen radicals, such as methyl, ethyl, propyl, isopropyl andthe like.

The compounds of the present invention exhibit pharmacological activityas anticonvulsants, muscle relaxants and sedative agents.

The following reaction schemes set forth the preparative steps requiredto produce the novel compounds of the present invention. ##STR3##wherein R₁, R₂ and X are as above and R is the leaving group of theformula ##STR4## wherein R₅ and R₆ separately are lower alkyl, phenyl ortogether with the nitrogen form a substituted or unsubstitutedheterocyclic ring of 3-8 atoms, such as pyrrolidine, piperidine andmorpholine. ##STR5## wherein R₁, R₂, R₄ and X are as above.

Scheme 1

I→ii

compounds of formula I which are benzodiazepine-2,4-diones are knowncompounds, see, for example, South African Pat. No. 68/00,803, July 22,1968 or Chemical Abstracts, 70, 106579, 1969. The diones (I) areconverted to the methylamidines by reaction with methylamine andtitanium tetrachloride. This reaction is known in the art having beenpreviously set forth in Belgian Pat. No. 774873, Nov. 3, 1971 toBoehringer Ingelheim G.m.b.H.

ii→iv

nitrosation of the compounds of formula II is achieved by theutilization of nitrous acid or nitrosyl chloride in pyridine to formcompounds of the formula III. The reaction may be effected in solventssuch as aliphatic or aromatic hydrocarbons, e.g., ethers, benzene,toluene, etc., or especially chlorinated hydrocarbons such as methylenechloride. The temperature at which the reaction may be carried outranges from -30° C. to room temperature with, preferentially, thereaction temperature being about room temperature when utilizing nitrousacid and 0° C. when utilizing nitrosyl chloride.

I→iii

the compound of formula I may be reacted with a phosphorylating agentsuch as a dicyclicaminophosphinic halide, e.g., chloride, or abis-di-lower alkylaminophosphinic halide, e.g., chloride, aftertreatment with a strong base sufficient to generate the anion such asalkali metal alkoxides and alkali metal hydrides, e.g., sodium hydride,sodium methoxide or alkyl lithium compounds such as n-butyl lithium. Thereaction may be effected at temperatures of 0° C. to 100° C., preferablyat room temperature. The reaction is preferably carried out in anaprotic polar inert solvent, such as ethers, e.g., tetrahydrofuran anddioxane and tertiary amides such as dimethylformamide. Examples of theabove reaction may be found in Ning et al., Journal of OrganicChemistry, 41, 2724 and 2720 (1976).

Iii→v

the nucleophilic displacement of the compound of formula III with acarbanion of nitromethane leads to the nitromethylene compound V. Thedisplacement is carried out at temperatures of about -20° to about 100°C., with room temperature as most preferred. As in the above step, anaprotic polar inert solvent may be utilized to solubilize the reactioncompounds, e.g., THF, DMF, etc.

Iv→v

the compound of the formula IV is thereafter converted to thenitromethylene (V) compound by reaction with nitromethane in thepresence of a strong base such as lithium amide, sodium amide, lithiumhydride or preferably potassium-t-butoxide. The reaction may be carriedout utilizing an inert solvent such as dimethylformamide,dimethylsulfoxide and ethers such as tetrahydrofuran and dimethoxyethaneor mixtures thereof. The reaction temperature ranges from -20° to 100°C., but is preferably carried out at room temperature.

V→vi

the compound of the formula V thereafter undergoes a reduction stepfollowed by in situ ring closure by condensation. The reduction step ofthe reaction is carried out by utilizing hydrogen with a metal catalystsuch as platinum, palladium or nickel. Solvents for such a reductionstep include hydrocarbons such as alcohols, e.g., ethanol, ethers, e.g.,tetrahydrofuran, acetic acid, dimethylformamide, ethyl acetate ormixtures of the above. The reaction temperature ranges from roomtemperature to 50° C., with room temperature being preferred.

Vi→vii

the compound of formula VI is thereafter oxidized with either manganesedioxide or potassium permanganate to the unsaturated compound (VII).Solvents suitable for the oxidation step include any inert aromatic oraliphatic hydrocarbon such as benzene or xylene or chlorinatedhydrocarbons such as chlorobenzene. The temperature at which theoxidation takes place may range from 80° C. to 150° C. with thepreferred temperature being the reflux temperature of whatever solventis selected.

Iii or IV→VIII

The compounds either of formula III or of formula IV may be condensedwith the anion generated from malonic ester, e.g., of the formula##STR6## to produce a compound of formula VIII. The anion is generatedby deprotonating a malonic ester with a suitable strong base such asalkali metal or alkaline earth metal alkoxides, hydrides or amides. Thereaction of the formula IV compound with the malonic ester anion ispreferably effected in a solvent such as hydrocarbons, e.g., benzene,toluene, hexane, ethers, e.g., dioxane, THF, diethyl ether, DMF, DMSO,etc., at a range of below room temperature to 150° C., preferably 0° C.to 100° C., most preferably room temperature.

Viii→ix

the compound of formula VIII is thereafter subjected to a hydrolysis anddecarboxylation reaction utilizing an alkali metal hydroxide or analkaline metal hydroxide, such as sodium or potassium hydroxide orcalcium or barium hydroxide. The reaction is effected in a solvent suchas an alcohol, e.g., methanol or ethanol, or an ether, e.g.,dimethoxyethane or tetrahydrofuran. The temperature at which thereaction is run may vary between room temperature to reflux temperaturewith reflux (varying with the selected solvent) being preferred.

Ix→x

the compound of formula IX thereafter undergoes a nitrosation reactionwith a reagent such as nitrous acid, nitrosyl chloride or lower alkylnitrite. The solvents utilized in the reaction may be chlorinatedhydrocarbons, e.g., dichloromethane, chlorobenzene, acetic acid ormixtures of water or alcohols, e.g., methanol or ethanol, with theacetic acid being preferred. The reaction temperature may range from-20° C. to 100° C., but room temperature is preferred.

X→xi

the compound of formula X is thereafter reduced to the amino compound(XI) by utilizing either hydrogen with Raney nickel or zinc in aceticacid. Solvents for this reaction include chlorinated hydrocarbons, e.g.,dichloromethane, chlorobenzene, alcohols, e.g., methanol or ethanol,acetic acid, dimethylformamide, or ethers, e.g., tetrahydrofuran ordioxane. The reaction temperature may vary from room temperature to 80°C. with room temperature preferred when Raney nickel/H₂ is utilized andreflux temperature when zinc/acetic acid are utilized.

Xi→xii

the compound of the formula XI thereafter undergoes a ring closure bycondensation with an ortho ester of formula XIV, i.e., R₂ --C(OR₁)₃, oran orthoamide of formula XV, i.e., ##STR7## or amide acetal of formulaXVI, i.e., ##STR8## Solvents for this reaction include hydrocarbons,chlorinated hydrocarbons, alcohols, ethers, esters, DMF and acetic acid.The reaction may be carried out in the absence or presence of a catalystand in an inorganic or organic acid. The reaction temperature rangesfrom room temperature to reflux temperature of the solvent with thelatter being preferred.

Xii→xiii

the cyclized product (XII) is thereafter converted from the ester to theamide for example, to the tertiary amide, by reaction with lithiumchloride in hexaalkylphosphorous triamide, e.g., hexamethyl- orhexaethyl-phosphorous triamide. The reaction temperature may be between180° C. to 250° C. with 220°-230° C. as the preferred temperature. Othersynthetic procedures, well known in the art, used for the conversion ofesters to amides, may, if desired, also be utilized.

The compounds of the present invention exhibit pharmacological activityas anxiolytics, sedatives, muscle relaxants and anticonvulsants. Ascontemplated by this invention, the novel compounds of the presentinvention and their pharmaceutically acceptable salts can be embodied inpharmaceutical dosage formulations containing from about 0.1 to about200 mg., most preferably 1-100 mg., with the dosage adjusted to speciesand individual patient requirements. The novel compounds and theirpharmaceutically acceptable salts can be administered internally, forexample, parenterally or enterally, in conventional pharmaceuticaldosage forms. For example, they can be incorporated in conventionalliquid or solid vehicles such as water, gelatin, starch, magnesiumstearate, talc, vegetable oils and the like to provide tablets, elixirs,capsules, solutions, emulsions and the like according to acceptablepharmaceutical practices.

Preferred compounds of the present invention include the followingspecies. ##STR9##

The expression "pharmaceutically acceptable salts" is used to includeboth inorganic and organic pharmaceutically acceptable acids such ashydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, citric acid, formic acid, maleic acid, acetic acid,succinic acid, tartaric acid, methanesulfonic acid, paratoluenesulfonicacid and the like. Such salts can be formed quite readily by thoseskilled in the art, with the prior art and the nature of the compound tobe placed in salt form, in view.

The following examples are illustrative of the present invention and arenot intended to limit the scope thereof.

EXAMPLE 1 3,5-Dihydro-2-methylamino-5-phenyl-4H-1,5-benzodiazepin-4-one

A mixture of 28.8 g (0.114 m) of5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2,4-dione¹) in 1 l. oftetrahydrofuran and 200 ml of benzene was stirred in an ice bath andsaturated with methyl amine gas until all material was in solution. Amixture of 26 g (0.136 m) of titanium tetrachloride in 200 ml of benzeneand was added dropwise. When the addition was complete, the mixture wasstirred for 1/2 hour on ice. The ice bath was then replaced with aheating mantel and the mixture was stirred and refluxed for 2 hours,then cooled and diluted carefully with 200 ml of water.

The organic layer was decanted off and the residue was washed withtetrahydrofuran and dichloromethane. All the organic layers werecombined, dried and evaporated. The residue was crystallized fromdichloromethane/hexane to yield the end product with mp 180°-183°.

For analysis, the material was recrystallized fromdichloromethane/hexane to give colorless crystals with mp 181°-183°.

Anal. Calcd. for C₁₆ H₁₅ N₃ O: C, 72.43; H, 5.70; N, 15.84. Found: C,72.37; H, 5.73; N, 16.13.

EXAMPLE 27-Chloro-3,5-dihydro-2-(N-nitrosomethylamino)-5-phenyl-4H-1,5-benzodiazepin-4-one

(A) A rapidly stirred solution of 40 g (0.134 m) of7-chloro-3,5-dihydro-2-methylamino-5-phenyl-4H-1,5-benzodiazepin-4-one.sup.2)in 400 ml of dichloromethane and 40 ml of pyridine was cooled for 15minutes on an ice bath. Nitrosyl chloride gas was then introduced acrossthe surface of the mixture until all starting material was consumedaccording to thin layer chromatogram. The mixture was then washed withwater and saturated sodium bicarbonate solution, dried and evaporatedunder reduced pressure. The residue was dissolved in 300 ml of tolueneand again evaporated. Crystallization of the residue from ether/hexaneyielded end product with mp 123°-126° C.

The analytical sample was recrystallized from methylene chloride/hexaneto give light yellow crystals with same mp.

Anal. Calcd. for C₁₆ H₁₃ ClN₄ O₂ : C, 58.46; H, 3.99; N, 17.04. Found:C, 58.51; H, 3.76; N, 17.21.

(B) Sodium nitrite, 21.26 g (0.308 m) was added over a period of 20 minto a stirred solution of 71 g (0.237 m) of7-chloro-3,5-dihydro-2-methylamino-5-phenyl-4H-1,5-benzodiazepin-4-onein 500 ml of acetic acid. Following the addition, the mixture wasstirred for 1 hr at room temperature and was then diluted with 1.5 l. ofwater. The precipitated product was collected, washed with water anddissolved in methylene chloride. The solution was washed with saturatedsodium bicarbonate solution, dried over sodium sulfate and evaporated.The residue was crystallized from ether to yield yellow crystals with mp121°-124°. A second crop was obtained from the mother liquor.

EXAMPLE 33,5-Dihydro-2-(N-nitrosomethylamino)-5-phenyl-4H-1,5-benzodiazepin-4-one

Sodium nitrite, 5.9 g (0.086 moles), was added in 3 portions over aperiod of 30 minutes to a stirred solution of 18.9 g (0.071 m) of3,5-dihydro-2-methylamino-5-phenyl-4H-1,5-benzodiazepin-4-one in 200 mlof acetic acid. After the addition was completed, the mixture wasstirred for 20 minutes at room temperature and was then diluted withwater and extracted with methylene chloride. The methylene chlorideextracts were combined, washed with saturated sodium bicarbonatesolution, dried and evaporated. The residue was crystallized from etherto yield product. Additional material was obtained from the concentratedmother liquors. For analysis, the material was recrystallized from ethylacetate/hexane, mp 139°-140° C.

Anal. Calcd. for C₁₆ H₁₄ N₄ O₂ : C, 65.30; H, 4.79; N, 19.03. Found: C,65.50; H, 4.65; N, 19.24.

EXAMPLE 47-Chloro-5-phenyl-1,2,3,4-tetrahydro-2-nitromethylene-5H-1,5-benzodiazepin-4-one

Potassium t-butoxide, 10.24 g (0.092 moles) was added to a mixture of250 ml of dimethylformamide and 50 ml of nitromethane. After stirring atroom temperature for 15 min under nigrogen, 25 g (0.076 m) of7-chloro-3,5-dihydro-2-(N-nitrosomethylamino)-5-phenyl-4H-1,5-benzodiazepin-4-onewas added and stirring was continued for an additional 19 hours. Themixture was acidified with acetic acid and diluted with water. Theprecipitate was filtered off, washed with water and recrystallized frommethylene chloride/ethanol to give pale yellow crystals with mp259°-261°.

For analysis the product was recrystallized from the same solvents, mp260°-262°.

Anal. Calcd. for C₁₆ H₁₂ ClN₃ O₃ : C, 58.46; H, 3.37; N, 12.78. Found:C, 58.58; H, 3.40; N, 12.93.

EXAMPLE 55-Phenyl-1,2,3,4-tetrahydro-2-nitromethylene-5H-1,5-benzodiazepin-4-one

Potassium t-butoxide, 3.15 g (0.0281 moles) was added to a mixture of 70ml of dimethylformamide and 14 ml of nitromethane. After stirring for 30min at room temperature under nitrogen, 6.9 g (0.0234 moles) of3,5-dihydro-2-(N-nitrosomethylamino)-5-phenyl-4H-1,5-benzodiazepin-4-one,was added and stirring was continued for 48 hours. The mixture wasacidified with acetic acid and diluted with water. The precipitate wascollected, washed with water and recrystallized from methylenechloride/ethanol to yield end product with mp 231°-234°.Recrystallization for analysis from the some solvents raised the meltingpoint to 233°-235°.

Anal. Calcd. for C₁₆ H₁₃ N₃ O₃ : C, 65.08, H, 4.44; N, 14.23. Found: C,65.06; H, 4.42; N, 14.33.

EXAMPLE 68-Chloro-1-methyl-6-phenyl-3,3a,4,6-tetrahydro-5H-imidazo[1,5-a][1,5]benzodiazepin-5-one

7-Chloro-5-phenyl-1,2,3,4-tetrahydro-2-nitromethylene-5H-1,5-benzodiazepin-4-one18.3 g. (0.055 mole) was dissolved in 300 ml of dimethylformamide bygentle heating on a steam bath. The solution was cooled to roomtemperature and 400 ml of ethanol and 55 g of Raney nickel were added.The mixture was hydrogenated at atmospheric pressure for 21 hours. Thecatalyst was filtered off and washed well with tetrahydrofuran andmethylene chloride. The filtrate was evaporated and the residue wasdissolved in 325 ml of xylene, and 40 ml of triethyl orthoacetate wasadded to the solution which was then refluxed for 1 hour. The mixturewas evaporated and the residue was crystallized from ethyl acetate toyield end product with mp 248°-251°. The analytical sample wasrecrystallized from methylene chloride/ethyl acetate to give colorlesscrystals with mp 250°-252°.

Anal. Calcd. for C₁₈ H₁₆ N₃ OCl: C, 66.36; H, 4.95; N, 12.90. Found: C,66.11; H, 4.94; N, 12.98.

EXAMPLE 7 8-Chloro-4,6-dihydro-1-methyl-6-phenyl-5H-imidazo[1,5-a] [1,5]benzodiazepin-5one

A mixture of 7.2 g. (0.022 moles) of8-chloro-1-methyl-6-phenyl-3,3a,4,6-tetrahydro-5H-imidazo[1,5]benzodiazepin-5-one,45 g. of activated manganese dioxide and 1.5 l. of toluene was stirredand refluxed for 45 minutes. The manganese dioxide was filtered off andwashed well with tetrahydrofuran and methylene chloride. The filtratewas evaporated and the residue was crystallized from ethyl acetate toyield end product with mp 276°-278° C.

For analysis, the product was recrystallized from methylenechloride/ethyl acetate to give colorless crystals with mp 276°-278°.

Anal. Calcd. for C₁₈ H₁₄ ClN₃ O: C, 66.77; H, 4.36; N, 12.98. Found: C,66.52; H, 4.12; N, 12.89.

EXAMPLE 8 4,6-Dihydro-1-methyl-6-phenyl-5H-imidazo[1,5-a][1,5]benzodiazepin-5-one

Raney nickel, 11 g, was added to a solution of 3.5 g. (0.0118 m) of5-phenyl-1,2,3,4-tetrahydro-2-nitromethylene-5H-1,5-benzodiazepin-4-onein 50 ml of tetrahydrofuran, and 150 ml of ethanol. The mixture was thenhydrogenated at atmospheric pressure for a period of 20 hours. Thecatalyst was filtered off and washed with tetrahydrofuran and methylenechloride. The filtrate was evaporated and the remaining oil (3.1 g.) wasdissolved in 250 ml of xylene and 6.2 ml of triethylorthoacetate. Afterheating to reflux with stirring for 30 min, the reaction mixture wasevaporated. The residue was dissolved in 200 ml of toluene and 19 g ofactivated manganese dioxide was added to the solution. The mixture wasstirred and refluxed for 30 min. The manganese dioxide was filtered offand washed well with tetrahydrofuran and methylene chloride. Thefiltrate was evaporated, and the residue was crystallized from ethylacetate to yield crystals with mp 217°-220°. For analysis, the materialwas recrystallized from methylene chloride/ethyl acetate to givecolorless crystals with mp 221°-223°.

Anal. Calcd. for C₁₈ H₁₅ N₃ O: C, 74.72; H, 5.23; N, 14.52. Found: C,74.94; H, 5.22; N, 14.69.

EXAMPLE 97-Chloro-5-phenyl-1,2,3,5-tetrahydro-2-dimethoxymalonylidene-4H-1,5-benzodiazepin-4-one

Potassium t-butoxide, 31.9 g. (0.285 m) was added to a solution of 156ml of dimethyl malonate in 750 ml of dimethylformamide. After stirringunder nitrogen for 15 min, 78 g. (0.237 m) of7-chloro-3,5-dihydro-2-(N-nitrosomethylamino)-5-phenyl-4H-1,5-benzodiazepin-4-onewas added and stirring was continued for 24 hrs at room temperaturefollowed by additional 3 hrs at 50°-60°. The cool reaction mixture wasacidified with glacial acetic acid and the product was crystallized byslow dilution with 1.2 l. of water. The crystals were collected andwashed with water, ethanol and ether to yield the colorless product withmp 154°-158°. The analytical sample was recrystallized from methanol, mp155°-158°.

Anal. Calcd. for C₂₀ H₁₇ ClN₂ O₅ : C, 59.93; H, 4.28; N, 6.99. Found: C,60.15; H, 4.28; N, 6.95.

EXAMPLE 10 7-Chloro-5-phenyl-1,2,3,4-tetrahydro-2-[(methoxycarbonyl)methylene]-5H-1,5-benzodiazepin-4-one

A mixture of 19.8 g. (0.049 m) of7-chloro-5-phenyl-1,2,3,5-tetrahydro-2-dimethoxymalonylidene-4H-1,5-benzodiazepin-4-one,5.93 g. (0.148 m) of sodium hydroxide, and 1.5 l. of methanol, wasstirred and refluxed for 2 hours. About 1 l. of methanol was evaporatedoff and the remaining mixture was diluted with 1.5 l. of water. Theprecipitate was filtered, washed with water and then recrystallized frommethylene chloride/methanol to yield end product with mp 199°-201° C.The analytical sample was recrystallized from the same solvents, mpunchanged.

Anal. Calcd. for C₁₈ H₁₅ ClN₂ O₃ : C, 63.07; H, 4.41; N, 8.17. Found: C,63.19; H, 4.39; N, 8.03.

EXAMPLE 117-Chloro-3,5-dihydro-alpha-hydroxyimino-4H-5-phenyl-1,5-benzodiazepin-4-one-2-aceticacid, methyl ester

Sodium nitrite, 5.21 g. (0.075 m) was added in 3 portions over 15 min toa stirred mixture of 19.9 g. (0.058 m) of7-chloro-5-phenyl-1,2,3,4-tetrahydro-2[(methoxycarbonyl)methylene]-5H-1,5-benzodiazepin-4-one,and 300 ml of acetic acid. The mixture was stirred for an additional 15min at which time the product was precipitating out, and then dilutedwith water. The precipitate was filtered, washed with water, sucked dryand recrystallized from tetrahydrofuran to yield product with mp271°-273°. The analytical sample was recrystallized from tetrahydrofuranto give pale yellow crystals with the same mp.

Anal. Calcd. for C₁₈ H₁₄ ClN₃ O₄ : C, 58.15; H, 3.80; N, 11.30. Found:C, 58.34; H, 3.97; N, 11.30.

EXAMPLE 12 Methyl8-chloro-4,6-dihydro-1-methyl-6-phenyl-5H-imidazo-[1,5-a]1,5]benzodiazepin-5-one-3-carboxylate

A mixture of 135 ml of acetic acid and 5 g. (0.0134 m) of7-chloro-3,5-dihydro-alpha-hydroxyimino-4H-5-phenyl-1,5-benzodiazepin-4-one-2-aceticacid, methyl ester was heated just to reflux, and then cooled to 45° C.Methylene chloride, 675 ml, and 27 g of zinc dust were added to themixture, which was then refluxed for 20 min. The zinc was filtered offand washed with tetrahydrofuran. The filtrate was evaporated to drynessunder vacuum with the water bath temperature kept below 50° C. Theresidue was dissolved in 320 ml of ethyl acetate and 13.5 ml oftriethylorthoacetate and the mixture was refluxed for 1 min. The residuewas crystallized from ethyl acetate to yield end product having a mp of217°-221°. The product was recrystallized from methylene chloride/ethylacetate for analysis to give colorless crystals with the same mp.

Anal. Calcd. for C₂₀ H₁₆ ClN₃ O₃ : C, 62.91; H, 4.22; N, 11.0. Found: C,62.83; H, 4,31; N, 10.91.

EXAMPLE 138-Chloro-4,6-dihydro-6-phenyl-5-oxo-1,N,N-trimethyl-5H-imidazo [1,5-a][1,5]benzodiazepin-3-carboxamide

A mixture of 1.2 g. of methyl8-chloro-4,6-dihydro-1-methyl-6-phenyl-5-oxo-5H-imidazo[1,5-a][1,5]benzodiazepin-3-carboxylate, 2 g. of lithium chloride and 12 ml ofhexamethyl phosporic triamide was stirred and heated up to 230°. As soonas this temperature was reached, the reaction mixture was cooled andpartitioned between methylene chloride and water. The organic phase waswashed with water, dried over sodium sulfate and evaporated.Crystallization of the residue from ether yielded the end product whichwas recrystallized from ethyl acetate/hexane for analysis, mp 213°-215°.

Anal. Calcd. for C₂₁ H₁₉ ClN₄ O₂ : C, 63.88; H, 4.85; N, 14.19. Found:C, 63.81; H, 4.81; N, 14.20.

EXAMPLE 148-Chloro-4,6-dihydro-6-phenyl-5-oxo-N,N-dimethyl-5H-imidazo[1,5-a][1,5]benzodiazepin-3-carboxamide

As described in previous example,8-chloro-4,6-dihydro-6-phenyl-5-oxo-5H-imidazo[1,5-a][1,5]benzodiazepine-3-carboxylic acid, methyl ester was converted to thedimethylamide, mp. 255°-257°.

EXAMPLE 15

    __________________________________________________________________________    Capsule Formulation                                                                              mg/capsule                                                 __________________________________________________________________________    1. 8-chloro-4,6-dihydro-1-methyl-6-                                                              1.0  5.0  10.0 40.0                                         phenyl-5H-imidazo[1,5-a] [1,5] benzo-                                         diazepin-5-one                                                               2. Lactose         149.0                                                                              182.5                                                                              215.0                                                                              260.0                                       3. Cornstarch      40.0 50.0 60.0 80.0                                        4. Magnesium Stearate                                                                            2.0  2.5  3.0  4.0                                         5. Talc            8.0  10.0 12.0 16.0                                        Total              200 mg.                                                                            250 mg.                                                                            300 mg.                                                                            400 mg.                                     __________________________________________________________________________

Procedure

1. Mix items 1-3 in a suitable mixer. Mill through suitable mill.

2. Mix with items 4 and 5 and fill on capsule machine.

EXAMPLE 16

    __________________________________________________________________________    Wet Granulation Tablet Formulation                                                               mg/tablet                                                  __________________________________________________________________________    1. 8-chloro-4,6-dihydro-1-methyl-6-                                                              1.0  5.0  10.0 40.0                                         phenyl-5H-imidazol[1,5-a] [1,5] benzo-                                        diazepin-5-one                                                               2. Lactose         195.0                                                                              230.0                                                                              264.0                                                                              273.0                                       3. Pregelatinized Starch                                                                         12.5 15.0 17.5 20.0                                        4. Cornstarch      25.0 30.0 35.0 40.0                                        5. Modified Starch 12.5 15.0 17.5 20.0                                        6. Magnesium Stearate                                                                            4.0  5.0  6.0  7.0                                         Total              250 mg.                                                                            300 mg.                                                                            350 mg.                                                                            400 mg.                                     __________________________________________________________________________

Procedure

1. Mix items 1-5 in a suitable mixer, granulate with water, Dryovernight in an oven. Mill through a Fitzpatrick mill.

2. Mix with item 6 and compress on a suitable press.

EXAMPLE 17

    __________________________________________________________________________    Direct Compression Tablet Formulation                                                            mg/tablet                                                  __________________________________________________________________________    1. 8-chloro-4,6-dihydro-1-methyl-6-                                                              1.0  5.0  10.0 40.0                                         phenyl-5H-imidazol[1,5-a] [1,5] benzo-                                        diazepin-5-one                                                               2. Lactose, Anhydrous DIG                                                                        127.0                                                                              142.5                                                                              182.0                                                                              216.0                                       3. Microcrystalline Cellulose                                                                    40.0 50.0 60.0 80.0                                        4. Modified Starch 10.0 12.5 15.0 20.0                                        5. Cornstarch      20.0 25.0 30.0 40.0                                        6. Magnesium Stearate                                                                            2.0  2.5  3.0  4.0                                         Total              200 mg.                                                                            250 mg.                                                                            300 mg.                                                                            400 mg.                                     __________________________________________________________________________

Procedure

1. Mix items 1-5 in a suitable mixer for 1 to 15 minutes.

2. Add item 6 and mix for 5 minutes. Compress on a suitable press.

EXAMPLE 18

    __________________________________________________________________________    Wet Granulation Tablet Formulation                                                               mg/tablet                                                  __________________________________________________________________________    1. 8-chloro-4,6-dihydro-1,N,N-trimethyl-                                                         1.0  5.0  10.0 40.0                                         6-phenyl-5H-[1,5a] [1,5] benzodiazepin-                                       5-one-3-carboxamide                                                          2. Lactose         195.0                                                                              230.0                                                                              264.0                                                                              273.0                                       3. Pregelatinized Starch                                                                         12.5 15.0 17.5 20.0                                        4. Cornstarch      25.0 30.0 35.0 40.0                                        5. Modified Starch 12.5 15.0 17.5 20.0                                        6. Magnesium Stearate                                                                            4.0  5.0  6.0  7.0                                         Total              250 mg.                                                                            300 mg.                                                                            350 mg.                                                                            400 mg.                                     __________________________________________________________________________

Procedure

1. Mix items 1-5 in a suitable mixer, granulate with water. Dryovernight in an oven. Mill through a Fitzpatrick mill.

2. Mix with item 6 and compress on a suitable press.

EXAMPLE 19

    __________________________________________________________________________    Direct Compression Tablet Formulation                                                            mg/tablet                                                  __________________________________________________________________________    1. 8-chloro-4,6-dihydro-1,N,N-trimethyl-                                                         1.0  5.0  10.0 40.0                                         6-phenyl-5H-[1,5a] [1,5] benzodiazepin-                                       5-one-3-carboxamide                                                          2. Lactose, Anhydrous DTG                                                                        127.0                                                                              142.5                                                                              182.0                                                                              216.0                                       3. Microcrystalline Cellulose                                                                    40.0 50.0 60.0 80.0                                        4. Modified Starch 10.0 12.5 15.0 20.0                                        5. Cornstarch      20.0 25.0 30.0 40.0                                        6. Magnesium Stearate                                                                            2.0  2.5  3.0  4.0                                         Total              200 mg.                                                                            250 mg.                                                                            300 mg.                                                                            400 mg.                                     __________________________________________________________________________

Procedure

1. Mix items 1-5 in a suitable mixer for 1 to 15 minutes.

2. Add item 6 and mix for 5 minutes. Compress on a suitable press.

EXAMPLE 20

    __________________________________________________________________________    Capsule Formulation                                                                              mg/capsule                                                 __________________________________________________________________________    1. 8-chloro-4,6-dihydro-1,N,N-trimethyl-                                                         1.0  5.0  10.0 40.0                                         6-phenyl-5H-[1,5-a] [1,5] benzodiazepin-                                      5-one-3-carboxamide                                                          2. Lactose         149.0                                                                              182.5                                                                              215.0                                                                              260.0                                       3. Cornstarch      40.0 50.0 60.0 80.0                                        4. Magnesium Stearate                                                                            2.0  2.5  3.0  4.0                                         5. Talc            8.0  10.0 12.0 16.0                                        Total              200 mg.                                                                            250 mg.                                                                            300 mg.                                                                            400 mg.                                     __________________________________________________________________________

Procedure

1. Mix items 1-3 in a suitable mixer. Mill through suitable mill.

2. Mix with items 4 and 5 and fill on capsule machine.

We claim:
 1. A process to produce a compound of the formula ##STR10##wherein X is hydrogen or halogen; R₁ is hydrogen, halogen ortrifluoromethyl; R₂ is hydrogen or lower alkyl; and R₃ is hydrogenwhichcomprises A. reacting a compound of the formula ##STR11## wherein R₁ andX are as above with methylamine in the presence of titaniumtetrachloride; B. nitrosating the product of (A) with nitrous acid ornitrosyl chloride in pyridine in the presence of an aromatic oraliphatic hydrocarbon solvent at a temperature of from about -30° C. toroom temperature; C. reacting the product of (B) with nitromethane inthe presence of a strong base selected from the group consisting oflithium amide, sodium amide, lithium hydride or potassium t-butoxide atfrom -20° C. to 100° C., or alternatively; D. reacting a compound offormula I above with a phosphorylating agent selected from the groupconsisting of a dicyclicaminophosphinic or bis-di-loweralkylaminophosphinic halide in the presence of a strong base selectedfrom the group consisting of an alkai metal alkoxide or hydroxide atfrom 0° C. to 100° C; E. nucleophilically displacing the phosphinicleaving group of D with the carbanion of nitromethane at about -20degrees C. to about 100 degrees C. in an aprotic polar inert solvent; F.reducing in the presence of hydrogen and a metal catalyst and in situcyclizing the produce of (C) or (E) by condensation in the presence ofan inert hydrocarbon solvent at room temperature to 50° C.; and G.oxidizing the product of (F) to the unsaturated end product by reactionwith manganese dioxide or potassium permanganate in an inert aromatic oraliphatic hydrocarbon at from 80° C. to 150° C.